1. Field of the Invention
The present invention is directed, in part, to the discovery that valienamine-related disaccharide compounds reduce, in vivo, the degree of inflammation arising from a secondary immune response in a mammal due to antigen exposure (challenge).
Specifically, this invention is directed to methods of reducing the degree of inflammation arising from a secondary immune response in a mammal due to antigen exposure (challenge) by the administration of valienamine-related compounds and to pharmaceutical compositions comprising such valienamine-related compounds.
2. References
The following publications and patent application are cited in this application as superscript numbers at the relevant portion of the application:
1. Ippolito et al., U.S. patent application Ser. No. 08/081,214 for "TIME DEPENDENT ADMINISTRATION OF OLIGOSACCHARIDE GLYCOSIDES RELATED TO BLOOD GROUP DETERMINANTS HAVING A TYPE I OR TYPE II CORE STRUCTURE IN REDUCING INFLAMMATION IN A SENSITIZED MAMMAL ARISING FROM EXPOSURE TO AN ANTIGEN" filed Jun. 25, 1993 PA1 2. Smith and Ziola, Immunology 58:245 (1986) PA1 3. Ogawa et al., J. Chem. Soc. Perkin Trans 1:2675-2680 (1988) PA1 4. Cerny et al., Collection Czechoslav. Chem. Commun. 39:1391-1396 (1974) PA1 5. Hayashida et al., J. Carbohydrate Chemistry 7(1):83-94 (1988) PA1 6. Ray and Matteson, Tetrahedron Lett. 21:449 (1980) PA1 7. Kameda et al., J. Antibio. 37:1301-1307 (1984) PA1 8. Takeuchi et al., Chem. Pharm. Bull 38(7):1970-1972 (1990) PA1 9. Ogawa et al., J. Org. Chem. 48:1203-1207 (1983) PA1 10. Paulson et al., Liebigs Ann Chem. 125-131 (1987) PA1 where R.sub.2 is selected from the group consisting of--H and --OH; and pharmaceutically acceptable salts thereof. PA1 pharmaceutically acceptable salts thereof. PA1 pharmaceutically acceptable salts thereof. PA1 pharmaceutically acceptable salts thereof. PA1 pharmaceutically acceptable salts thereof.
All of the above publications and patent applications are herein incorporated by reference in their entirety to the same extent as if each individual publication or patent application was specifically and individually indicated to be incorporated by reference in its entirety.
3. State of the Art
The administration to mammals of different oligosaccharide glycosides has been disclosed in the art to reduce inflammation in the mammal arising from a variety of conditions such as injury, infection, exposure to an antigen, etc. These disclosures are based on the fact that an integral step in the inflammatory process in a mammal is the adherence of leukocytes to one or more selectins and the discovery that such oligosaccharide glycosides adhere/bind to one or more selectins involved in the inflammatory response thereby interfering with the binding of the leukocyte to those selectins.
Allowed U.S. patent application Ser. No. 08/081,214.sup.1 discloses that in order to reduce inflammation in the case of an antigen challenge (exposure) in a sensitized mammal, the oligosaccharide glycoside must be administered after initiation of the mammal's secondary immune response to the antigen challenge but at or prior to one-half the period of time where the mammal experiences maximal inflammatory response.
However, it was found that after administration of oligosaccharide glycosides to a mammal, the oligosaccharides were quickly cleared from the mammalian system. Accordingly, it was desired to identify pseudo-oligosaccharides which would not be cleared from the mammalian system as quickly as oligosaccharide glycosides and still retain activity in reducing the degree of inflammation in a mammal arising from initiation of a mammal's secondary immune response due to antigen exposure. In other words, compounds were desired that were more resistant to degradation in the mammalian body and able to withstand denaturation in the stomach and/or removal from the blood stream by action of glycosidases.
It is known in the art that the pseudo-aminosugars, validamine, valienamine and valiolamine, show inhibition of .alpha.-glucosidases, sucrase and maltase in vitro and of sucrase, maltase, glucoamylase, isomaltase and trehalase in vivo. (Takeuchi et al., (1990).sup.8 Ogawa et al., J. Org. Chem. 48:1203-1207 (1983)).sup.9 also describe the compound valienamine-.alpha.-1,4-glucose. However, it was not known if such pseudo-aminosugars or pseudo-disaccharides containing such sugars would be effective in reducing the degree of inflammation arising from a secondary immune response in a mammal due to antigen exposure.
As shown herein valienamine-related disaccharide compounds are able to reduce the degree of inflammation arising from a secondary immune response. Further advantages of the present invention will become apparent from the following description of the invention with reference to the attached drawings.